A healthy kidney provides the vital function of clearing toxins from the blood and retaining everything else. The kidney achieves this essentially through a two-step process. First, the blood passes a mechanical filter. Cells and large solutes stay in the bloodstream while smaller solutes and a large portion of the plasma volume pass through the membrane. Second, cell-driven active transport and passive diffusion combine to create a re-absorption step, where almost all of the fluid and its constituents other than specific waste products, namely urea, are driven back into the bloodstream. The waste flows out as urine.
In a kidney, the two-step process is completed in millions of parallel units. Each unit functions independently of the others. In each unit, pressure-driven filtration takes place in a network of capillaries known as the glomerulus. The glomerulus is generally spherical and a few hundred microns in diameters. It is surrounded by Bowman's Capsule, which captures all materials that pass through the filter. Filtrate passes from there to the proximal tubule, Loop of Henle, distal tubule, and collecting duct, in that order. Active transport and diffusion take place in these systems. The process is highly efficient, excreting highly concentrated waste without loss of water or other vital blood components. The complete unit and accompanying blood vessels is known as the nephron.
Numerous conventional approaches for performing artificial mechanical filtration of blood exist. Once such approach is hemodialysis, which is widely used for treating patients with renal failure. In that approach, the patient's blood is caused to flow into a dialysis cartridge. The cartridge contains a porous membrane which allows only small particles to pass through. A fluid, known as the dialysate, is pumped through the device on the other side of the membrane from the blood. Small particles diffuse from the blood into the dialysate, which is discarded as waste.
Hemofiltration is a variation of hemodialysis. In this hemodialysis, blood is pumped through a dialysis cartridge. No dialysate is used. Blood plasma carrying small particles passes through the membrane and out of the device, and this fluid is discarded as waste. Combinations of hemofiltration and hemodialysis exist, where varying ratios of blood and dialysate are pumped through the cartridge.
Blood filtration can also be performed in a microfluidic device as described in U.S. Ser. No. 10/983,213 entitled “Micromachined Bilayer Unit of Engineered tissues,” published as U.S. Patent Application Publication No. 20050202557. According to one approach disclosed in that application, a multi-layered micromachined device is constructed with a membrane similar to that of a dialysis cartridge, and filtration takes place between the layers of the device.
Another approach for filtering blood is disclosed in U.S. Ser. No. 10/316,000, entitled “Methods and Compositions of Bioartificial Kidney Suitable for Use In Vivo or Ex Vivo,” publication as U.S. Patent Application Publication No. 20030119184. In this application, appropriate renal cells are grown on a hollow-fiber dialysis chamber and are shown to perform active transport. Such a device replicates the function of the renal proximal tubule, but does not replicate the elements beyond that in the filtrate flow path.
The approaches discussed above suffer from drawbacks. For example, they are not able to fully replicate nephron functions. More particularly, they are not able to replicate the nephron's function to form concentrated urine.
In hemodialysis, waste fluid is generated at approximately 500-700 milliliters per minute. In hemofiltration, waste fluid is generated at approximately 100 milliliters per minutes. As these procedures are performed for hours at a time, the patient is typically connected to a multi-gallon waste receptacle. The plasma fluid removed in hemofiltration must additionally be replaced, requiring more hardware and a reserve of plasma.
Existing bioartificial kidneys represent an improvement by reportedly re-absorbing 50% of the waste fluid. For comparison, a functioning kidney re-absorbs approximately 99% of fluid that leaves through the glomerulus. Without the ability to re-absorb a comparable percentage of fluid, existing approaches generate large amounts of waste, and therefore, are unlikely to lead to a useful wearable device.
Additionally, size-selective filtration performed by the approaches discussed above does not replicate selective filtration of the kidney and other cell-mediated metabolic functions. Survival rates and overall health of dialysis patients are poor in general, and this is attributed to dialysis not performing specific filtration and other kidney functions. Existing devices are thrombogenic so that Heparin or other anti-clotting agent are administered to the patient. There are numerous negative side effects to this treatment. Also, these systems typically require mechanical pumping to regulate the flows through the filter. Existing devices typically require pumping apparatus to drive blood (and dialysate, if appropriate) through the filtration.
Accordingly, there is a need for an improved approach that can more fully replicate kidney function. More specifically, there is a need for an approach that can more fully replicate nephron's formation of concentrated urine.